Priority Research Papers:
Orthogonal targeting of EGFRvIII expressing glioblastomas through simultaneous EGFR and PLK1 inhibition
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Ying Shen1,2,3,*, Jie Li1,*, Masayuki Nitta4,*, Diahnn Futalan1, Tyler Steed1, Jeffrey M. Treiber1, Zack Taich1, Deanna Stevens5, Jill Wykosky5, Hong-Zhuan Chen2,3, Bob S. Carter1, Oren J. Becher6, Richard Kennedy7, Fumiko Esashi8, Jann N. Sarkaria9, Frank B. Furnari5, Webster K. Cavenee5, Arshad Desai5 and Clark C. Chen1
1 Center for Theoretical and Applied Neuro-Oncology, Moores Cancer Center, Division of Neurosurgery, University of California San Diego, La Jolla, CA, USA
2 Department of Pharmacology and Chemical Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
3 Collaborative Innovation Center for Translational Medicine, Shanghai Jiao Tong University School of Medicine, Shanghai, China
4 Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
5 San Diego Branch, Ludwig Institute for Cancer Research, University of California San Diego, La Jolla, CA, USA
6 Departments of Pediatrics and Pathology, Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC, USA
7 Centre for Cancer Research and Cell Biology, Queen’s University of Belfast, Belfast, UK
8 The Sir William Dunn School of Pathology, University of Oxford, Oxford, UK
9 Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA
* These authors contributed equally to the manuscript
Clark C. Chen, email:
Keywords: EGFR, EGFRvIII, glioblastoma, synthetic lethality
Received: April 12, 2015 Accepted: April 20, 2015 Published: May 05, 2015
We identified a synthetic lethality between PLK1 silencing and the expression of an oncogenic Epidermal Growth Factor Receptor, EGFRvIII. PLK1 promoted homologous recombination (HR), mitigating EGFRvIII induced oncogenic stress resulting from DNA damage accumulation. Accordingly, PLK1 inhibition enhanced the cytotoxic effects of the DNA damaging agent, temozolomide (TMZ). This effect was significantly more pronounced in an Ink4a/Arf(-/-) EGFRvIII glioblastoma model relative to an Ink4a/Arf(-/-) PDGF-β model. The tumoricidal and TMZ-sensitizing effects of BI2536 were uniformly observed across Ink4a/Arf(-/-) EGFRvIII glioblastoma clones that acquired independent resistance mechanisms to EGFR inhibitors, suggesting these resistant clones retain oncogenic stress that required PLK1 compensation. Although BI2536 significantly augmented the anti-neoplastic effect of EGFR inhibitors in the Ink4a/Arf(-/-) EGFRvIII model, durable response was not achieved until TMZ was added. Our results suggest that optimal therapeutic effect against glioblastomas requires a “multi-orthogonal” combination tailored to the molecular physiology associated with the target cancer genome.
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